Deep Resequencing of the 1q22 Locus in Non-Lobar Intracerebral Hemorrhage.

OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown. METHODS: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk. RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk. INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337.

Sleep duration and brain MRI measures: Results from the SOL-INCA MRI study.

INTRODUCTION: Sleep duration has been associated with dementia and stroke. Few studies have evaluated sleep pattern-related outcomes of brain disease in diverse Hispanics/Latinos. METHODS: The SOL-INCA (Study of Latinos-Investigation of Neurocognitive Aging) magnetic resonance imaging (MRI) study recruited diverse Hispanics/Latinos (35-85 years) who underwent neuroimaging. The main exposure was self-reported sleep duration. Our main outcomes were total and regional brain volumes. RESULTS: The final analytic sample included n = 2334 participants. Increased sleep was associated with smaller brain volume (ßtotal_brain  = -0.05, p < 0.01) and consistently so in the 50+ subpopulation even after adjusting for mild cognitive impairment status. Sleeping >9 hours was associated with smaller gray (ßcombined_gray  = -0.17, p < 0.05) and occipital matter volumes (ßoccipital_gray  = -0.18, p < 0.05). DISCUSSION: We found that longer sleep duration was associated with lower total brain and gray matter volume among diverse Hispanics/Latinos across sex and background. These results reinforce the importance of sleep on brain aging in this understudied population. HIGHLIGHTS: Longer sleep was linked to smaller total brain and gray matter volumes. Longer sleep duration was linked to larger white matter hyperintensities (WMHs) and smaller hippocampal volume in an obstructive sleep apnea (OSA) risk group. These associations were consistent across sex and Hispanic/Latino heritage groups.

WITHDRAWN: Advances in Neurovascular Research: Scientific Highlights from the 15th World Stroke Congress.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2024.107614. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Efficacy and Safety of Mechanical Thrombectomy in Elderly and Non-Elderly Patients with Large Vessel Occlusion Stroke A Systematic Review and Meta-Analysis.

INTRODUCTION Mechanical thrombectomy (MT) is recommended for large vessel occlusion (LVO) stroke. However, most of the studies that investigated the superiority of MT over best medical management (BMM) alone included preponderantly non-elderly patients. Thus, there is uncertainty in relation to the efficacy of MT in the elderly. We aim to compare the effect of BMM to BMM plus (MT) among elderly and non-elderly patients with (LVO). METHODS We performed a systematic search of medical databases from inception to April 2023 to identify randomized studies that reported the functional outcome at 90 days by age for patients with LVO treated with MT vs. BMM. Patients were divided into elderly (>70 or >80 years, depending on the cut-off used in each study) and non-elderly. Outcomes were defined as excellent (modified Rankin Scale [mRS]≤1), good (mRS≤3), poor (mRS≥5), or death. Effect sizes were calculated by using random effects meta-analyses. Results were represented by odds ratio (OR) and their 95% confidence intervals (95% CI). RESULTS A total of 2,195 patients were included in the analysis (≥70 years, 7 trials, n= 696; ≥80 years, 2 trials, n=139). Non-elderly patients treated with MT had higher odds of excellent outcome (OR 3.05; 95% CI 2.23-4.18) and good outcome (OR 2.70; 95% CI 1.94-3.74), and lower odds of poor outcome (OR 0.54; 95% CI 0.40-0.72) and death (OR 0.63; 95% CI 0.41-0.96). Similarly, elderly patients treated with MT had higher odds of excellent (OR 2.39; 95% CI 1.05-5.45) and good outcomes (OR 2.18; 95% CI 1.43-3.33) and lower odds of poor outcome (OR 0.48; 95% CI 0.33-0.70) and mortality (OR 0.50; 0.26-0.95). When outcomes were analyzed by age subgroups, MT was associated with higher odds of good outcome in patients ≥70 years (OR 1.95, 95% CI 1.26-3.03) and ≥80 years (OR 4.43, 95% CI 1.02-19.23). DISCUSSION/CONCLUSION MT increases the likelihood of achieving a good outcome in elderly and non-elderly patients without increasing the risk of severe disability or death. MT, when otherwise clinically indicated, should be considered over BMM alone in both age groups.

The Role of Serum Monocytes and Tissue Macrophages in Driving Left Ventricular Systolic Dysfunction and Cardiac Inflammation Following Subarachnoid Hemorrhage.

BACKGROUND: Neurocardiogenic injury is common after aneurysmal subarachnoid hemorrhage (aSAH) despite low prevalence of preexisting cardiac disease. Potential mechanisms include autonomic dysregulation due to excess catecholamines as well as systemic inflammation. Understanding how inflammation contributes to cardiac dysfunction may aid in identifying novel therapeutic strategies. Here, we investigated serum leukocytes as predictors of left ventricular systolic dysfunction in patients with aSAH. We also investigated increased cardiac macrophages in an animal model of SAH and whether immunomodulatory treatment could attenuate this inflammatory response. METHODS: We retrospectively analyzed 256 patients with aSAH admitted to University of Illinois Hospital between 2013 and 2019. Our inclusion criteria included patients with aSAH receiving an echocardiogram within 72 h of admission. Our primary outcome was echocardiographic evidence of systolic dysfunction. We performed multinomial regression and receiver operating curve analysis. We also used the endovascular perforation model of SAH in male Sprague-Dawley rats to assess for myocardial inflammation. Two days after surgery, hearts were collected and stained for the macrophage marker Iba-1. We compared the presence and morphology of macrophages in cardiac tissue isolated from SAH animals and sham controls treated with and without the immunomodulatory agent fingolimod. RESULTS: Of 256 patients with aSAH, 233 (91.0%) underwent echocardiography within 72 h of admission. Of 233, 81 (34.7%) had systolic dysfunction. Patients had baseline differences in the presence of hypertension, alcohol use, and admission Glasgow Coma Scale and Hunt-Hess score. On multivariable analysis, total leukocytes (odds ratio 1.312, p < 0.001), neutrophils (odds ratio 1.242, p = 0.012), and monocytes (odds ratio 6.112, p = 0.008) were independent predictors of reduced systolic function, whereas only monocytes (odds ratio 28.014, p = 0.030) predicted hyperdynamic function. Within the rodent heart, there were increased macrophages after SAH relative to controls, and this was attenuated by fingolimod treatment (p < 0.0001). CONCLUSIONS: Increased serum leukocytes are associated with abnormal left ventricular systolic function following aSAH. The strongest independent predictor of both reduced and hyperdynamic systolic function was increased monocytes. Increased cardiac macrophages after experimental SAH can also be targeted by using immunomodulatory drugs.

Efficacy and Safety of Using Dual Versus Monotherapy Antiplatelet Agents in Secondary Stroke Prevention: Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

BACKGROUND: Dual antiplatelet treatment (DAPT) with aspirin plus clopidogrel for a limited time is recommended after minor noncardioembolic stroke. METHODS: We performed a meta-analysis of all major studies that compared the efficacy and safety of DAPT versus monotherapy for the secondary prevention of recurrent stroke or transient ischemic attack. The primary outcomes were stroke and the composite of stroke, transient ischemic attack, acute coronary syndrome, and death from any cause. The safety outcome was major hemorrhage. Relative risk (RR) and 95% CIs were calculated. Heterogeneity was assessed by I2 and Cochrane Q statistics. RESULTS: The analysis included 27 358 patients, the quality of evidence was moderate to low, and the heterogeneity for all the comparisons was low (I2≤25%). Compared with monotherapy, DAPT reduced the risk of recurrent stroke (RR, 0.71 [95% CI, 0.63-0.81]) and composite outcome (RR, 0.76 [95% CI, 0.69-0.83]) but increased the risk of major bleeding (RR, 2.17 [95% CI, 1.45-3.25]). In the subgroup analysis, ≤30 days of DAPT increased the risk of hemorrhage relative to monotherapy (RR, 1.94 [95% CI, 1.08-3.52]). In the sensitivity analysis, the risk for hemorrhage with ≤30 days of DAPT after excluding the combination of aspirin plus ticagrelor was comparable to monotherapy (RR, 1.42 [95% CI, 0.77-2.60]). However, the risk for stroke recurrence and composite outcomes in the subgroup and sensitivity analyses remain decreased compared with monotherapy. CONCLUSIONS: DAPT decreases the risk of recurrent stroke and composite events compared with monotherapy. DAPT increases the risk of major hemorrhage, except if the treatment is limited to 30 days and does not include the combination of aspirin plus ticagrelor.

Use of Marijuana: Effect on Brain Health: A Scientific Statement From the American Heart Association.

Marijuana is perceived as a harmless drug, and its recreational use has gained popularity among young individuals. The concentration of active ingredients in recreational formulations has gradually increased over time, and high-potency illicit cannabinomimetics have become available. Thus, the consumption of cannabis in the general population is rising. Data from preclinical models demonstrate that cannabinoid receptors are expressed in high density in areas involved in cognition and behavior, particularly during periods of active neurodevelopment and maturation. In addition, growing evidence highlights the role of endogenous cannabinoid pathways in the regulation of neurotransmitter release, synaptic plasticity, and neurodevelopment. In animal models, exogenous cannabinoids disrupt these important processes and lead to cognitive and behavioral abnormalities. These data correlate with the higher risk of cognitive impairment reported in some observational studies done in humans. It is unclear whether the effect of cannabis on cognition reverts after abstinence. However, this evidence, along with the increased risk of stroke reported in marijuana users, raises concerns about its potential long-term effects on cognitive function. This scientific statement reviews the safety of cannabis use from the perspective of brain health, describes mechanistically how cannabis may cause cognitive dysfunction, and advocates for a more informed health care worker and consumer about the potential for cannabis to adversely affect the brain.

Identifying Best Practices to Improve Evaluation and Management of In-Hospital Stroke: A Scientific Statement From the American Heart Association.

This scientific statement describes a path to optimizing care for patients who experience an in-hospital stroke. Although these patients are in a monitored environment, their evaluation and treatment are often delayed compared with patients presenting to the emergency department, contributing to higher rates of morbidity and mortality. Reducing delays and optimizing treatment for patients with in-hospital stroke could improve outcomes. This scientific statement calls for the development of hospital systems of care and targeted quality improvement for in-hospital stroke. We propose 5 core elements to optimize in-hospital stroke care: 1. Deliver stroke training to all hospital staff, including how to activate in-hospital stroke alerts. 2. Create rapid response teams with dedicated stroke training and immediate access to neurological expertise. 3. Standardize the evaluation of patients with potential in-hospital stroke with physical assessment and imaging. 4. Address barriers to treatment potentially, including interfacility transfer to advanced stroke treatment. 5. Establish an in-hospital stroke quality oversight program delivering data-driven performance feedback and driving targeted quality improvement efforts. Additional research is needed to better understand how to reduce the incidence, morbidity, and mortality of in-hospital stroke.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Neurological Manifestations of Acute Porphyrias.

PURPOSE OF REVIEW: Porphyrias constitute a group of rare metabolic disorders that result in a deficiency of the heme biosynthetic pathway and lead to the accumulation of metabolic intermediaries. Patients with porphyria can experience recurrent neurovisceral attacks which are characterized by neuropathic abdominal pain and acute gastrointestinal symptoms, including nausea, vomiting, and constipation. Depending on the type of porphyria, patients can present with cutaneous manifestations, such as severe skin photosensitivity, chronic hemolysis, or evidence of neurologic dysfunction, including alterations in consciousness, neurovascular involvement, seizures, transient sensor-motor symptoms, polyneuropathy, and behavioral abnormalities. RECENT FINDINGS: More recently, cases of posterior reversible encephalopathy syndrome, cerebral vasoconstriction, and acute flaccid paralysis have also been described. While the exact pathogenic mechanisms linking the accumulation of abnormal heme biosynthetic intermediaries to neurologic manifestations have not been completely elucidated, it has been proposed that these manifestations are more common than previously thought and can result in permanent neurologic injury. This article reviews the basic principles of heme synthesis as well as the pathogenic mechanism of disease, presentation, and treatment of acute hepatic porphyrias with emphasis on those with neurologic manifestations.

Neurological Manifestations of Myocarditis.

PURPOSE OF REVIEW: The present review discusses the neurological complications associated with myocarditis of different etiologies. RECENT FINDINGS: Myocarditis can be idiopathic or caused by different conditions, including toxins, infections, or inflammatory diseases. Clinical findings are variable and range from mild self-limited shortness of breath or chest pain to hemodynamic instability which may result in cardiogenic shock and death. Several neurologic manifestations can be seen in association with myocarditis. Tissue remodeling, fibrosis, and myocyte dysfunction can result in heart failure and arrhythmias leading to intracardiac thrombus formation and cardioembolism. In addition, peripheral neuropathies, status epilepticus, or myasthenia gravis have been reported in association with specific types of myocarditis. Multiple studies suggest the increasing risk of neurologic complications in patients with myocarditis. Neurologists should maintain a high suspicion of myocarditis in cases presenting with both cardiovascular and neurological dysfunction without a clear etiology.

Navigating Antiplatelet Treatment Options for Stroke: Evidence-Based and Pragmatic Strategies.

PURPOSE OF REVIEW: The benefit of using antiplatelet monotherapy in acute ischemic stroke and secondary stroke prevention is well established. In the last few years, several large randomized trials showed that the use of short-term dual antiplatelet therapy in particular stroke subtypes may reduce the risk of recurrent ischemic events. The aim of this article is to provide a critical analysis of the current evidence and recommendations for the use of antiplatelet agents for stroke prevention. RECENT FINDINGS: Long-term therapy with aspirin, clopidogrel, or aspirin plus extended-release dipyridamole is recommended for secondary stroke prevention in patients with noncardioembolic ischemic stroke. Short-term dual antiplatelet therapy with aspirin and clopidogrel is superior to antiplatelet monotherapy in secondary stroke prevention when used in patients with mild noncardioembolic stroke or high-risk transient ischemic attack. Dual therapy, however, is associated with an increased risk of major bleeding, particularly when the treatment is extended for greater than 30 days. Similarly, aspirin plus ticagrelor is superior to aspirin monotherapy for the prevention of recurrent ischemic stroke, although this combination is associated with a higher risk of hemorrhagic complications when compared to other dual antiplatelet regimens. Among patients who carry CYP2C19 genetic polymorphisms associated with a slow bioactivation of clopidogrel, short-term treatment with aspirin plus ticagrelor is superior to aspirin plus clopidogrel for the reduction of recurrent stroke; however, the use of ticagrelor is associated with a higher risk of any bleeding. In patients with symptomatic intracranial stenosis, aggressive medical management in addition to dual antiplatelet therapy up to 90 days is recommended. Antiplatelet therapy has an essential role in the management of ischemic stroke. The specific antiplatelet regimen should be individualized based on the stroke characteristics, time from symptom onset, and patient-specific predisposition to develop hemorrhagic complications.

Bilirubin Encephalopathy.

PURPOSE OF REVIEW: Hyperbilirubinemia is commonly seen in neonates. Though hyperbilirubinemia is typically asymptomatic, severe elevation of bilirubin levels can lead to acute bilirubin encephalopathy and progress to kernicterus spectrum disorder, a chronic condition characterized by hearing loss, extrapyramidal dysfunction, ophthalmoplegia, and enamel hypoplasia. Epidemiological data show that the implementation of universal pre-discharge bilirubin screening programs has reduced the rates of hyperbilirubinemia-associated complications. However, acute bilirubin encephalopathy and kernicterus spectrum disorder are still particularly common in low- and middle-income countries. RECENT FINDINGS: The understanding of the genetic and biochemical processes that increase the susceptibility of defined anatomical areas of the central nervous system to the deleterious effects of bilirubin may facilitate the development of effective treatments for acute bilirubin encephalopathy and kernicterus spectrum disorder. Scoring systems are available for the diagnosis and severity grading of these conditions. The treatment of hyperbilirubinemia in newborns relies on the use of phototherapy and exchange transfusion. However, novel therapeutic options including deep brain stimulation, brain-computer interface, and stem cell transplantation may alleviate the heavy disease burden associated with kernicterus spectrum disorder. Despite improved screening and treatment options, the prevalence of acute bilirubin encephalopathy and kernicterus spectrum disorder remains elevated in low- and middle-income countries. The continued presence and associated long-term disability of these conditions warrant further research to improve their prevention and management.

Elevated Serum Leukocytes are Predictive of Cardiac Injury Following Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: Aneurysmal subarachnoid hemorrhage (aSAH) accounts for 5% of strokes but results in significant morbidity and mortality. In addition to systemic inflammation, up to half of patients develop cardiac injury; however, the relationship between systemic inflammation and cardiac injury after aSAH is unknown. We investigated changes in leukocyte counts in relation to cardiac dysfunction MATERIALS AND METHODS: We reviewed the records of consecutive patients with SAH at our large academic medical referral center. The inclusion criteria were aSAH and available cardiac troponin I (cTnI) levels within 48 h of admission. The primary outcome was cardiac injury, defined as cTnI ≥0.04 ng/mL (lab reference range 0.01-0.03 ng/mL). We compared baseline characteristics, including serum leukocyte counts and performed univariable and multivariable logistic regression analysis to determine whether changes in leukocyte subpopulations predict cardiac injury. RESULTS: Of 288 SAH patients, 250 met inclusion criteria. Of these, 116 (46.4%) had elevated cTnI. In univariable analysis, total leukocyte count (p < 0.001), absolute neutrophil count (ANC, p < 0.001), and absolute monocyte count (p = 0.013), were associated with elevated cTnI. in multivariable analysis, total leukocyte count (OR=1.079, p = 0.037) and ANC (OR=1.081, p = 0.044) remained predictors of elevated cTnI. Adjusted ANC distinguishes between aSAH patients with normal and elevated TnI (area under the curve=0.766, p < 0.001) with specificity of 89.2%. CONCLUSIONS: Elevated total leukocytes and ANC are independently associated with cardiac injury in aSAH. Systemic inflammatory responses after aSAH may play a role in cardiac dysfunction, warranting additional studies to further characterize how cardiac inflammation after aSAH drives subsequent morbidity and mortality.

Stroke Risk Factor Status and Use of Stroke Prevention Medications Among Hispanic/Latino Adults in HCHS/SOL.

BACKGROUND AND PURPOSE: We investigated the prevalence, awareness, and control of vascular risk factors (VRFs) and the use of antithrombotic and statin agents in HCHS (Hispanic Community Health Study)/SOL (Study of Latinos) participants with self-reported history of stroke or transient ischemic attack. METHODS: Sociodemographic characteristics, medications, and prevalence of different VRFs were recorded. VRF diagnoses and goals were based on the recommendations of professional organizations. Factors associated with optimal VRF control and use of antithrombotic and statin agents were investigated using multivariate logistic regression. RESULTS: The analysis included 404 participants (39% men). The prevalences of hypertension, dyslipidemia, and diabetes were 59%, 65%, and 39%, respectively. Among those who met the diagnostic criteria for these diagnoses, the frequencies of awareness were 90%, 75%, and 83%, respectively. In participants who were aware of their VRFs, the prevalences of controlled hypertension, dyslipidemia, and diabetes were 46%, 32%, and 54%. Approximately 46% of the participants were on antithrombotics, 39% on statins, and 26% on both. Only 38% of those with atrial fibrillation received anticoagulation. In multivariate analyses adjusted for baseline sociodemographic characteristics, older age was associated with uncontrolled hypertension and diabetes. Residing in the United States for ≥10 years and born in the United States were associated with uncontrolled diabetes, female sex with uncontrolled dyslipidemia, and lack of health insurance with decreased use of statins and hyperlipidemia. CONCLUSIONS: Hispanic/Latino adults in the United States have high prevalence and awareness of VRFs but low adherence to secondary stroke prevention strategies. Older adults, women, and uninsured people are vulnerable groups that may benefit from targeted interventions. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060344.

Cerebrovascular Complications Associated with Marijuana Use.

PURPOSE OF REVIEW: In the last few years, the attitude toward marijuana in many parts of the world has shifted from illicit to legalized for medical use and to decriminalized. In parallel, there has been a gradual increase in the consumption of this product in the general population, particularly among adolescents and young adults. Marijuana is generally perceived as a harmless drug. However, data obtained in observational studies and preclinical models have established associations between cannabis use and cardiovascular events. In addition, there is emerging evidence linking marijuana use to cerebrovascular complications. Here we provide a critical review of the literature with special emphasis on the association of cannabinoids with stroke and the possible pathogenic mechanisms involved. RECENT FINDINGS: Ischemic and hemorrhagic stroke have been described in association with cannabis use, particularly in young individuals. Cerebral infarction remains the most commonly reported stroke subtype seen in marijuana users. Several pathogenic mechanisms have been proposed to explain this association, including multifocal intracranial stenosis, reversible cerebral vasoconstriction syndrome, and coexisting vascular risk factors. Cannabis use is increasingly recognized in young individuals presenting with acute stroke. Our understanding of the pathogenic mechanisms associated with cannabis use and stroke is limited but rapidly evolving. Healthcare providers should educate patients about the potential cardiovascular and cerebrovascular complications related to marijuana or cannabinoids use.

Inflammasome Caspase-1 Activity is Elevated in Cerebrospinal Fluid After Aneurysmal Subarachnoid Hemorrhage and Predicts Functional Outcome.

BACKGROUND/OBJECTIVE: Subarachnoid hemorrhage (SAH) is a devastating neurological injury, further complicated by few available methods to objectively predict outcomes. With the recent shift in focus to neuroinflammation as a potential cause of adverse outcomes following SAH, we investigated the inflammasome-derived enzyme, caspase-1, as a potential biomarker for poor functional outcome. METHODS: SAH patients were recruited from a regional stroke referral center. Cerebrospinal fluid (CSF) samples from 18 SAH subjects were collected via an external ventricular drain and obtained as close as possible to admission (within 72 h). For control subjects, we collected CSF from 9 patients undergoing lumbar puncture with normal CSF. Caspase-1 activity was measured using commercially available luminescence assays. SAH subjects were categorized at hospital discharge into those with good outcomes (Glasgow Outcome Scale, GOS, of 4-5) and poor outcomes (GOS of 1-3). RESULTS: CSF analysis demonstrated a nearly seven-fold increase in caspase-1 activity in SAH patients compared to controls (p < 0.0001). Within the SAH group, 10 patients (55.6%) had good outcomes and 8 patients (44.4%) had poor outcomes. Mean caspase-1 activity in the poor outcome group was approximately three-times higher than the good outcome group (p = 0.001). Caspase-1 activity was significantly correlated with GOS score (r = - 0.705, p = 0.001). Receiver operating characteristic curve analysis showed that caspase-1 activity can accurately differentiate between patients with good versus poor functional outcome (area under the curve 0.944, p = 0.002). CONCLUSIONS: Inflammasome-derived caspase-1 activity is elevated in the CSF of SAH patients compared to controls and higher levels correlate with worse functional outcome.

Efficacy and Safety of PCSK9 Inhibitors in Stroke Prevention.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) interacts with the low-density lipoprotein (LDL) receptor and, by enhancing its degradation, has a pivotal role in the regulation of cholesterol homeostasis. Two fully humanized monoclonal antibodies targeting PCSK9, evolocumab and alirocumab, are available for clinical use. PCSK9 inhibitors reduce LDL-C 30% more than ezetimibe and 60% more than placebo when added to statins. This reduction in LDL-C is accompanied by a decrease in the risk of major cardiovascular and cerebrovascular events. However, questions have been raised in relation to the cost-effectiveness of these medications. In this article, we review the clinical evidence on the use of PCSK9 inhibitors in lowering LDL-C and their effect on cerebrovascular health.

Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the apolipoprotein E (APOE) gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and APOE genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest. METHODS: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and APOE genotype predict ICH recurrence. We then developed and validated a combined APOE-MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis. RESULTS: Cortical superficial siderosis, cerebral microbleed, and APOE ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all P<0.05). Combining APOE genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, P=0.033). In the MGH (training) data set, CSS, cerebral microbleed, and APOE ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH. CONCLUSIONS: Combining MRI and APOE genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined APOE-MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

Cortical priming strategies for gait training after stroke: a controlled, stratified trial.

BACKGROUND: Stroke survivors experience chronic gait impairments, so rehabilitation has focused on restoring ambulatory capacity. High-intensity speed-based treadmill training (HISTT) is one form of walking rehabilitation that can improve walking, but its effectiveness has not been thoroughly investigated. Additionally, cortical priming with transcranial direct current stimulation (tDCS) and movement may enhance HISTT-induced improvements in walking, but there have been no systematic investigations. The objective of this study was to determine if motor priming can augment the effects of HISTT on walking in chronic stroke survivors. METHODS: Eighty-one chronic stroke survivors participated in a controlled trial with stratification into four groups: 1) control-15 min of rest (n = 20), 2) tDCS-15 min of stimulation-based priming with transcranial direct current stimulation (n = 21), 3) ankle motor tracking (AMT)-15 min of movement-based priming with targeted movements of the ankle and sham tDCS (n = 20), and 4) tDCS+AMT-15 min of concurrent tDCS and AMT (n = 20). Participants performed 12 sessions of HISTT (40 min/day, 3 days/week, 4 weeks). Primary outcome measure was walking speed. Secondary outcome measures included corticomotor excitability (CME). Outcomes were measured at pre, post, and 3-month follow-up assessments. RESULTS: HISTT improved walking speed for all groups, which was partially maintained 3 months after training. No significant difference in walking speed was seen between groups. The tDCS+AMT group demonstrated greater changes in CME than other groups. Individuals who demonstrated up-regulation of CME after tDCS increased walking speed more than down-regulators. CONCLUSIONS: Our results support the effectiveness of HISTT to improve walking; however, motor priming did not lead to additional improvements. Upregulation of CME in the tDCS+AMT group supports a potential role for priming in enhancing neural plasticity. Greater changes in walking were seen in tDCS up-regulators, suggesting that responsiveness to tDCS might play an important role in determining the capacity to respond to priming and HISTT. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03492229. Registered 10 April 2018 - retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03492229 .